Heart disease is a leading cause of mortality and morbidity and an emerging public health problem in the developing world (Hunt et al., J. Am. Cell. Cardiol. 46:1116 (2005)). Acute injury to the heart commonly occurs following occlusion of a culprit blood vessel with subsequent death of dependent cardiac muscle. The mammalian heart heals by scar formation and the inability of the mammalian heart to regenerate cardiac muscle coupled with a predominantly fibrotic response to acute cardiac injury remains a fundamental biological problem to the therapy of heart disease.
The Wnt signaling system, comprising 19 lipophilic proteins in mammals (Gordon et al., J. Biol. Chem. 281:22429 (2006)), plays a critical role in wound repair and regeneration in simple systems such as planaria and hydra (Gurley et al., Science 319:323 (2008); Petersen et al., Science 319:327 (2008)). Wnts are developmentally important for cardiogenesis (Eisenberg et al., Dev. Biol. 293:305 (2006)) and Wnt antagonists exert anti-apoptotic effects on cardiac myocytes as well as affect scarring (Kobayashi et al., Nature Cell Biol. 11:46 (2009); Mirotsou et al., Proc. Natl. Acad. Sci. USA 104:1643 (2007)); however the precise physiological role of Wnts following acute cardiac injury remains unexplored.
Peripheral vascular disease affects 10-15% of the population in the US above the age of 65 years (Becker et al., J. Vasc. Interv. Radiol. 13:7 (2002)), and is a debilitating condition caused by atherosclerotic narrowing and restriction of arterial blood flow to the extremities. Chronic vascular insufficiency induces skin, muscle, and nerve damage and severely reduces functionality of the limbs. New blood vessel formation in the adult has been traditionally thought to arise from proliferation of existing blood vessels (angiogenesis) (Conway et al., Cardiovasc. Res. 49:507 (2001)) but a large body of literature suggests that de novo formation of blood vessels from endothelial progenitor cells (vasculogenesis) occurs in post natal life (Asahara et al., EMBO J. 18:3964 (1999); Takahashi et al., Nature Med. 5:434 (1999); Tepper et al., Blood (2004)).
Human endothelial progenitor cells (hEPCs) are known to participate in neovascularization of ischemic tissues (Asahara et al., EMBO J. 18:3964 (1999)). Patients with vascular disease have decreased number as well as function of EPCs but molecular strategies to enhance human EPC function remain unclear (Takahashi et al., Nature Med. 5:434 (1999)). Genes playing a critical role during development and organogenesis can exert therapeutic effects on postnatal organ dysfunction (Tepper et al., Blood (2004); Vasa et al., Circ. Res. 89:e1 (2001)). The Wnt signaling system plays a critical role in organogenesis, as well as postnatal processes such as carcinogenesis and wound repair (Nusse et al., Cell 31:99 (1982)).
The present invention addresses previous shortcomings in the art by disclosing the role of Wnt1 in both cardiac repair and angiogenesis in ischemic tissue. This discovery provides methods for treating cardiovascular disorders and injuries, including enhancing cardiac repair and increasing blood flow in ischemic tissues.